Figure 1.

Illustrates the interaction of at least six major neurotransmitter pathways involved in the Brain Reward Cascade (BRC). In the hypothalamus, environmental stimulation causes the release of serotonin, which in turn, via 5HT-2a receptors, activates (the green, equal sign) the subsequent release of opioid peptides into the hypothalamus. Then, the opioid peptides have two distinct effects, possibly via two different opioid receptors. (A) Inhibits (the red hash sign) through the Mu-opioid receptor (possibly via enkephalin) and projects to the substania nigra to GABAA neurons. (B) Stimulates (the green, equal sign) cannabinoid neurons (e.g., anandamide and 2-archydonoglcerol) through beta–endorphin-linked delta receptors, which in turn inhibit GABAA neurons at the substania nigra. Cannabinoids, primarily 2-archydonoglcerol, when activated, can also indirectly disinhibit (the red hash sign) GABAA neurons in the substania nigra through activation of G1/0 coupled to CB1 receptors. Similarly, glutamate neurons located in the Dorsal Raphe Nuclei (DRN) can indirectly disinhibit GABAA neurons in the substania nigra by activating GLU M3 receptors (the red hash sign). GABAA neurons, when stimulated, will, in turn, powerfully (the red hash signs) inhibit Ventral Tegmental Area (VTA) glutaminergic drive via GABAB 3 neurons. Finally, glutamate neurons in the VTA will project to dopamine neurons through NMDA receptors (the green, equal sign) to preferentially release dopamine at the NAc, shown as a bullseye indicating well-being (Blum et al. with permission).